Dermal delivery of amitriptyline for topical analgesia.

Amitriptyline, administered orally, is currently one of the treatment options for the management of neuropathic pain and migraine. Because of the physicochemical properties of the molecule, amitriptyline is also a promising candidate for delivery as a topical analgesic. Here we report the dermal delivery of amitriptyline from a range of simple formulations. The first stage of the work required the conversion of amitriptyline hydrochloride to the free base form as confirmed by nuclear magnetic resonance (NMR). Distribution coefficient values were measured at pH 6, 6.5, 7, and 7.4. Solubility and stability of amitriptyline were assessed prior to conducting in vitro permeation and mass balance studies. The compound demonstrated instability in phosphate-buffered saline (PBS) dependent on pH. Volatile formulations comprising of isopropyl alcohol (IPA) and isopropyl myristate (IPM) or propylene glycol (PG) were evaluated in porcine skin under finite dose conditions. Compared with neat IPM, the IPM:IPA vehicles promoted 8-fold and 5-fold increases in the amount of amitriptyline that permeated at 24 h. Formulations containing PG also appear to be promising vehicles for dermal delivery of amitriptyline, typically delivering higher amounts of amitriptyline than the IPM:IPA vehicles. The results reported here suggest that further optimization of topical amitriptyline formulations should be pursued towards development of a product for clinical investigational studies.

Palliative care for children and young people with stage 5 chronic kidney disease.

Death from stage 5 chronic kidney disease (CKD 5) in childhood or adolescence is rare, but something that all paediatric renal physicians and most paediatricians will encounter. In this paper, we present the literature on three key areas of palliative care practice essential to good clinical management: shared decision-making, advance care planning, and symptom management, with particular reference to CKD 5 where kidney transplant is not an option and where a decision has been made to withdraw or withhold dialysis. Some areas of care, particularly with regard to symptom management, have not been well-studied in children and young people (CYP) with CKD 5 and recommendations with regard to drug choice and dose modification are based on adult literature, known pharmacokinetics, and clinical experience.

Long-Term Daily Administration of Aprepitant for the Management of Intractable Nausea and Vomiting in Children With Life-Limiting Conditions: A Case Series.

BACKGROUND: Nausea and vomiting is a common symptom in children through their end of life journey. Aprepitant, a NK-1 antagonist, has become a potent weapon in the fight against chemo-induced nausea and vomiting. However, its use in palliative care for refractory nausea and vomiting has been limited due to limited experience or evidence of continuous use. Emerging evidence suggests that continuous use is not only safe, but also effective in patients with nausea and vomiting refractory to multiple lines of antiemetic therapy. METHODS: We conducted a single centre retrospective chart review of children receiving care from a specialist palliative care team who were given continuous daily aprepitant for nausea and vomiting and were unresponsive to at least two prior lines of antiemetic therapy. Parental reports of the impact of nausea on mobility and feeding were used as proxy efficacy markers. Duration of effect and toxicity was also evaluated. RESULTS: Ten children (eight with cancer as a primary diagnosis and two with noncancer diagnoses) received continuous aprepitant and all showed resolution of nausea and vomiting and an increased ability to mobilize and tolerate feeds. No adverse events noted. CONCLUSION: Our review suggests a role for aprepitant in management of refractory nausea and vomiting, demonstrating safety and efficacy. This case series is the first report of aprepitant use in this manner in the paediatric palliative care setting.

Investigation of binary and ternary solvent systems for dermal delivery of methadone.

Methadone appears to be a promising candidate for pain management. Previously, we conducted a comprehensive characterization study of methadone base and evaluated the dermal delivery of methadone from various neat solvents. Four solvents, namely d-limonene (LIM), ethyl oleate (EO), Transcutol® P (TC) and octyl salicylate (OSAL), were identified as the optimal neat solvents for skin delivery of the compound. To explore further approaches to improve methadone permeation, the present work investigated a range of binary and ternary vehicles. In vitro permeation studies in porcine skin confirmed that binary systems delivered significantly higher (p < 0.05) amounts of methadone through the skin compared with neat solvents. The highest skin permeation was observed for formulations composed of propylene glycol (PG) and TC. Nine formulations were subsequently examined in human skin. A good correlation (r2 = 0.80) for methadone permeation was obtained between porcine ear skin and human skin data. Solvent uptake studies indicated that the presence of PG not only increased methadone permeation but also TC permeation. The drug appears to "track" the permeation of TC. Future studies will expand further the range of potential vehicles for optimal delivery of the drug, that will ultimately to be investigated in clinical studies.

Preparation, Characterization and Dermal Delivery of Methadone.

The use of methadone for the management of pain has received great interest in recent years. Currently, oral and intravenous formulations are available for clinical use. Dermal delivery represents an attractive alternative route of administration for this drug as it is associated with comparatively fewer side effects. The first stage of the work was the preparation of methadone free base as this form of the drug is expected to permeate the skin to a greater extent than the hydrochloride salt. Subsequently the molecule was characterized with Nuclear Magnetic Resonance (NMR) and thermal analysis, the distribution coefficient was determined and solubility studies were conducted in a range of solvents. In vitro permeation and mass balance studies were conducted under finite dose conditions (5 µL/cm2) in porcine skin. The results confirmed the more favorable penetration of methadone free base compared with the salt. The highest cumulative amount of methadone (41 ± 5 µg/cm2) permeated from d-limonene (LIM). Ethyl oleate (EO), Transcutol® P (TC) and octyl salicylate (OSAL) also appear to be promising candidate components of dermal formulations for methadone base. Future work will focus on further formulation optimization with the objective of progressing to evaluation of prototype dosage forms in clinical trials.

Mobilisation of haematopoietic stem cells in paediatric patients, prior to autologous transplantation following administration of plerixafor and G-CSF.

Previous chemotherapy and radiation exposure can make adequate stem cell mobilisation prior to autologous transplant extremely difficult in paediatrics. Plerixafor, a selective reversible CXCR4 antagonist interferes with CXCR4 interaction with Stromal cell-derived factor 1 alpha (SDF-1). Combination with granulocyte-colony stimulating factor (G-CSF) amplifies G-CSF affects in mobilising haematopoietic stem cells. Whilst licensed for use with G-CSF for enhancement of mobilisation of haematopoietic stem cells in adults, paediatric data for use of plerixafor remain limited. We present a retrospective review of outcomes seen with plerixafor and G-CSF to mobilise stem cells heavily pre-treated paediatric patients with cancer.

Standard dosing of tacrolimus leads to overexposure in pediatric renal transplantation recipients.

Tacrolimus dosage in pediatric RTRs is empirically based on weight. There is evidence that adolescents are at greater risk of toxicity than young children on this dosing regimen. We investigated the rate of tacrolimus overexposure within the first three wk post-transplantation in pediatric RTRs receiving tacrolimus 0.15 mg/kg twice daily. Of 63 RTRs studied, 41 (65.1%) experienced a tacrolimus level above the therapeutic range (supratherapeutic), the majority (48.8%) on days two to four post-transplant. Patients with supratherapeutic levels were older (14.2 vs. 9.9 yr, p = 0.016), taller (146.7 vs. 126.5 cm, p = 0.029), larger (1.36 vs. 1.01 m(2), p = 0.039) and heavier (44.1 vs. 29.3 kg, p = 0.043) and by day 12 were receiving much lower tacrolimus doses than those without supratherapeutic levels (0.425 vs. 0.198 mg/kg/day, p = 0.0002). Supratherapeutic levels were more common among white (British) children than other ethnic groups (74 vs. 45%, p = 0.02). There were no observed differences in rates of patient or graft survival, or acute rejection during the three-yr study period. Adolescent patients appear to be at greater risk of excessive tacrolimus dosing on a standard regimen. We therefore outline a regimen restricting tacrolimus dosage given to larger/older patients, but emphasize the need for a prospective randomized trial to define optimal dosing.